1. Field of the Invention
The present invention relates to novel 4-hydroxypiperidine derivatives, a method for manufacturing thereof, and a pharmaceutical composition comprising at least one of the derivatives as active ingredients, in particular an antiarrythmic agent capable of oral administration.
2. Description of Related Art
The heart can regularly beat when the excitation initiated at the sinus node conducts in a correct order. Arrythmia is generated when abnormal excitation and conduction to the heart are caused. Accordingly, the mechanism of onset of arrythmia is categorized into three groups of (1) abnormal excitation (2) abnormal conduction of excitation and (3) a combination of abnormal excitation and abnormal conduction of excitation.
Vaughan Williams, Singh and Houswirth have categorized antiarrythmic agents into four classes based on their action in the first half of 1970""s. Since then, this classificationxe2x80x94namely the Vaughan Williams classificationxe2x80x94has been utilized as a standard classification of the antiarrythmic agents. This classification method is excellent in that it briefly expresses features of pharmacological action of various antiarrythmic agents, and has been utilized by many physicians. This classification method roughly classifies the antiarrythmic agents into four classes of the class I to class IV.
The antiarrythmic agents classified into the class I are medicines which have mainly a sodium channel blocking activity, and reduce the maximum upstroke velocity of depolarization at the 0-th phase of the action potential, thereby reducing the conduction speed. The class I agents are further classified into sub-classes of Ia, Ib and Ic based on their effects on the action potential duration. The class I agents are featured in reduction of the cardiac contractility as a result of reduced intracellular calcium concentration due to activation of a sodium/calcium exchange mechanism, because the intracellular sodium concentration is reduced by blocking the sodium channel. Reduction of the cardiac contractility is one of crucial adverse effects of the class I antiarrythmic agents comparable to a proarrhythmic activity directly related to suppression of conduction due to the sodium channel blocking activity.
The antiarrythmic agents belonging to the class II are medicines which mainly have a xcex2-receptor blocking activity. Stimulation of the xcex2 (xcex21)-receptor in the cardiac muscle cells with catecholamines activates adenylate cyclase, enhances production of cyclic AMP and increases the inward calcium current. As a result, physiological automaticity of the sinus node as well as abnormal automaticity in the morbid cardiac muscle are exacerbated. Action potential duration is also shortened by activating various ion channels related to repolarization. Although the class II antiarrythmic agents are effective against the arrhythimia related to the sympathetic nerve by their antagonistic activity against the action of catecholamines, adverse effects such as suppression of cardiac function due to xcex2-receptor blocking activity is worried.
The antiarrythmic agents belonging to the class III are defined as the medicines with a primary action to retard repolarization and prolong of the action potential duration. These agents suppress arrythmia by prolonging refractory period as a result of prolongation of the action potential duration. It was made clear from recent studies that blocking action on the potassium channel is mainly responsible for the principal action of such agent, and a term xe2x80x9cpottasium channel blockerxe2x80x9d is currently synonymous with the class III agent. The class III agents are advantageous over the class I agents in that the former shows no suppression on cardiac contractility. On the other hand, xe2x80x9ctorsades de pointesxe2x80x9d as a result of a prolonged QT interval is a crucial and potentially lethal adverse effect common to the class III agents.
The antiarrythmic agents classified into the class IV is defined as medicines the main action of which is the blocking of the calcium channel. Although the agents are used for treating arrythmia caused by acceleration of automaticity in the sinus node and arrythmia related to the atrioventricular node, an antiarrythmic agent, for example, verapamil may weaken contraction force of the cardiac muscle.
In the Cardiac Arrythmia Suppression Trial (CAST) operated in 1989 in USA, Flecainide and Encainide belonging to the class I antarrythmic agents were used for post-myocardial infarction patients with silent and mild symptoms of ventricular extrasystole, and it was found that incidence of sudden death increases in the group administered with test drugs (Echt, D. A. et al., The new England Journal of Medicine, Vol. 324, pp.781-788, 1991). In other words, it was shown that suppression of ventricular extrasystole by the class I agents does not always suppress severe arrythmia such as ventricular fibrillation that is considered to cause sudden death. This research report aroused the need of paying attention to an appropriate use of the antiarrythmic agents, besides affording novel antiarrythmic agents to be developed. In place of conventional chemicals represented by powerful sodium channel blockers that have been used in the CAST study and suppress depolarization process of the cardiac muscle, potassium channel blockers that prolong the refractory period by prolonging the repolarization process have been expected to be the antiarrythmic agents for preventing sudden death. Clinical trials with amiodarone and sotalol at an early stage have accelerated this trend, and the potassium channel blocker without severe side-effects of amiodarone (for example, interstitial pneumonia and fibrosis of the lung) has been largely expected. However, developments of d-sotalol, E-4031 and sematilide have been suspended since it was proved that the incidence of xe2x80x9ctorsades de pointesxe2x80x9d accompanied by the QT prolongation was unexpectedly high in clinical trials in Japan as well as those in the USA and Europe with large scale in addition to the increase of mortality by these drugs. No antiarrythmic agent that can suppress sudden death of the arrythmia patients with basal diseases such as ischemic heart diseases and heart failure while avoiding the severe side-effects of amiodarone (for example, interstitial pneumonia and fibrosis of the lung) have been discovered in the present time. The large problems involved in drug therapy of arrythmia are (1) the class I and class III agents that affect conduction velocity and action potential duration by acting on the normal cardiac muscle cannot be safe antiarrythmic agents since they have proarrythmic action, and (2) the class II and class IV agents are only effective to limited symptoms of arrythmia. Accordingly, developments of novel type of antiarrythmic agents that are highly safe while avoiding the drawbacks of the antiarrythmic agents belonging to the class I to class IV classification are desired.
The sodium current normally observed in the excitable cells is rapidly inactivated after being promptly activated by a stimulus (depolarization), and thus the observed current is a transient inward current. The class I agent suppresses this transient sodium current, and decreases the maximum upstroke velocity of depolarization at the 0-th phase of the action potential to reduce the conduction velocity. However, some kinds of the sodium current are slowly or seldom inactivated, and these currents are considered to be involved in adjustment of physiological excitability of the neurons and cardiac myocytes. This sort of current is called as a persistent sodium current. This current is suggested to be involved in abnormal excitability of the neurons (for example, epileptic attack and ischemia) and morbidity of the cardiac myocytes (for example, onset of arrythmia), as reported by Segal, M. M. et al. (Journal of Neurophysiology, Vol. 77, pp. 3021-3034, 1997) and Ju, Y-K et al. (Journal of Physiology, Vol. 497, No. 2, pp. 337-347, 1996).
While lidocaine and quinidine are reported as the compounds for suppressing the persistent sodium current in the cardiac muscle (Ju, Y-K et al., British Journal of Pharmacology, Vol. 107, pp. 311-316, 1992), these compounds belong to the class I agent, and exhibit no specificity since they suppress the persistent sodium current as well as the transient sodium current. While phenytoin is reported to suppress these currents in the neurons (Segal et al., Journal of Neurophysiology, Vol. 77, pp. 3021-3034, 1997), phenytoin also has no specificity since it is categorized in the class I antiarrythmic agent.
Although 4-hydroxypiperidine derivatives have been reported to be the compounds having an analgesic activity in Japanese Patent Application Laid-open No. Sho 50-36471, an antiarrythmic action as described in the compound according to the present invention has not been disclosed therein. Although piperidine derivatives having an antiarrythmic activity have been disclosed in Japanese Patent Application Laid-open No. Sho 59-225161, the compounds have different structures from the compounds according to the present invention, and are suspected of having side-effects adverse on the activity of the normal cardiac muscle. Therefore, the compounds of the publication have not been developed as commercially available drugs. While Japanese National Patent Publication No. Hei 6-50093 discloses 4-substituted piperidine derivatives having the calcium blocking activity as neuro protective agents, the antiarrythmic activity as disclosed in the compounds according to the present invention has not been disclosed.
Not only desired pharmaceutical activities but also long-term safety are required in the development of medicines. In addition, severe criteria in various tests on absorption, distribution, metabolism and excretion should be satisfied. For example, problems to be examined and solved include interaction among the drugs, desentitization and tolerance, absorption at the digestive tract after oral administration, transfer speed into the small intestines, absorption velocity and first pass effect, internal organ barrier, binding to proteins, induction of drug metabolizing enzymes, the excretion pathway, clearance in the body and the methods of application (application sites, methods and objects). However, compounds satisfying all these requirements can be seldom found.
The antiarrythmic agent also involves such general problems as described above in developing as a medicine. The antiarrythmic agent is further required to avoid several problems as hitherto described such as proarrythmic activity, cardiac depression, torsades de pointes accompanied by prolongation of the QT interval, and increased incidence of sudden death.
The object of the present invention is to provide a novel compounds having an antiarrythmic activities with less side-effect and high grade of safety. Another object of the present invention is to provide methods for manufacturing the compounds Ad and to provide medicines and pharmaceutical compositions containing the compounds. In particular, the object of the present invention is to provide a drug, particularly an anti-arrythmic agent, capable of orally administering to mammals including humans, wherein at least one problem in the conventional art, for example, an proarrythmic action, a cardiac depression and torsades de pointes accompanied by a prolonged QT interval involved in the conventional drugs have been conquered. The medicines also have less proarrythmic action and cardiac depression so that conduction and action potential duration of the normal cardiac myocytes are not affected, and sudden death can be prevented.
The inventors of the present invention have found that, through intensive studies for obtaining chemicals having an excellent antiarrythmic action with high safety, novel 4-hydroxypiperidine derivatives and salts thereof have a suppressing action against contracture of the isolated cardiac muscle caused by veratrine, oral administration of the chemicals is effective in an ischemia-reperfusion model, have no effects on the normal activity in cardiac myocytes, and have less adverse effects while being highly safe, thereby completing the present invention.
The first embodiment of the present invention is to provide a compound represented by the formula (I): 
(wherein A represents a phenyl group, naphthyl group or monocyclic aromatic heterocyclic group each substituted by R1 and R2; R1 and R2 each independently represent groups arbitrarily selected from a group comprising hydrogen atom, halogen atom, trifluoromethyl group, cyano group, lower alkoxycarbonyl group, amino group unsubstituted or mono- or di-substituted by lower alkyl group, lower alkanoylamino group unsubstituted or substituted by fluorine atom, unprotected or protected hydroxyl group, lower alkoxy group, lower alkyl group, trifluoromethoxy group, nitro group, phenyl group, phenoxy group, unprotected or protected carboxyl group, carbamoyl group unsubstituted or mono- or di-substituted by lower alkyl group, lower alkanoyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group and sulfamoyl group unsubstituted or mono- or di-substituted by lower alkyl group, or R1 and R2 together represent alkylenedioxy group; R3 represents hydrogen atom or lower alkyl group; R4 represents hydrogen atom, lower alkyl group or lower alkanoyl group; R5 and R6 each independently represent a group arbitrarily selected from a group comprising hydrogen atom, halogen atom, lower alkoxy group unsubstituted or mono-substituted by unprotected or protected hydroxyl group, lower alkyl group unsubstituted or mono-substituted by unprotected or protected hydroxyl group, phenoxy group, lower alkenyloxy group or unprotected or protected hydroxyl group; X represents a single bond, a group: xe2x80x94CH(OH)xe2x80x94, oxygen atom or carbonyl group; Y represents lower alkylene group, lower alkylidene group or benzylidene group substituted by R1, Y may form 5- or 6-membered ring together with X and carbon atoms on a benzene ring when A is phenyl group; Z represents a single bond or methylene group unsubstituted or substituted by a group arbitrarily selected from a group comprising a lower alkyl group, lower alkoxy group or unprotected or protected hydroxyl group; and R7 and R8 each independently represent hydrogen atom or lower alkyl groups, provided that a case that R5 and R6 simultaneously represent hydrogen atoms is excluded) and pharmaceutically acceptable salts thereof and a pharmaceutical composition containing these compounds as active ingredients.
Preferable substituents or preferable combinations thereof in the compound represented by the formula (I) are shown below. However, the present invention is by no means restricted thereto.
A is preferably phenyl group or thienyl group each substituted by R1 and R2, more preferably phenyl group substituted by R1 and R2 or an unsubstituted thienyl group. In addition, it is preferable that A is phenyl group substituted by R1 and R2, and R1 is bound to a para-position (4-position) relative to xe2x80x94Xxe2x80x94.
R1 and R2 each are preferably hydrogen atom, halogen atom, trifluoromethyl group, cyano group, lower alkoxycarbonyl group, lower alkanoylamino group unsubstituted or substituted by fluorine atom, lower alkoxy group, lower alkyl group, trifluoromethoxy group, nitro group or lower alkylthio group, and more preferably hydrogen atom, halogen atom, trifluoromethyl group, cyano group, lower alkoxycarbonyl group or trifluoromethoxy group.
As the combinations of R1 and R2, it is preferable that R1 is hydrogen atom, halogen atom, trifluoromethyl group, cyano group, lower alkoxycarbonyl group, lower alkanoylamino group unsubstituted or substituted by fluorine atom, lower alkoxy group, lower alkyl group, trifluoromethoxy group, nitro group or lower alkylthio group, and R2 is hydrogen atom or halogen atom. It is more preferable that R1 is hydrogen atom, halogen atom, trifluoromethyl group, cyano group, lower alkoxycarbonyl group or trifluoromethoxy group, and R2 is hydrogen atom or halogen atom.
R3 is preferably hydrogen atom.
R4 is preferably lower alkyl group or lower alkanoyl group, more preferably lower alkyl group.
R5 is preferably lower alkoxy group, lower alkyl group or phenoxy group, more preferably C2-6 alkoxy group, and further preferably straight chaine or branched C2-4 alkoxy group.
R6 is preferably hydrogen atom, halogen atom, unprotected or protected hydroxyl group or lower alkyl group unsubstituted or mono-substituted by unprotected or protected hydroxyl group, and more preferably hydrogen atom.
As the combination of R5 and R6, it is preferable that R5 is C2-6 alkoxy group, and R6 is hydrogen atom, and it is more preferable that R5 is straight chian or branched C2-4 alkoxy group, and R6 is hydrogen atom.
R5 is preferably bound to a para-position (4-position) relative to xe2x80x94NR4xe2x80x94.
X is preferably a single bond or a group: xe2x80x94CH(OH)xe2x80x94, and more preferably a single bond.
Y is preferably C1-2 alkylene group or benzylidene group substituted by R1, and more preferably methylene group or benzylidene group substituted by R1.
Y preferably forms indanyl group when A is a phenyl group and 5- to 6-membered ring is formed together with X and carbon atoms on the benzene ring.
Z is preferably a single bond or methylene group unsubstituted or substituted by hydroxyl group, and more preferably methylene group.
R7 and R8 each are preferably hydrogen atoms.
As the combination of the substituents is preferable that the bonding position of R5 is at the para-position (4-position) relative to the group xe2x80x94NR4xe2x80x94, R7 and R8 each are hydrogen atom, X is a single bond, and Y is C1-2 alkylene group or benzylidene group substituted by R1.
It is preferable that A is phenyl group or thienyl group each substituted by R1 and R2, R4 is lower alkyl group, and Z is a single bond or methylene group.
It is preferable that R1 is hydrogen atom, halogen atom, trifluoromethyl group, cyano group, lower alkoxycarbonyl group or trifluoromethoxy group, R2 is hydrogen atom or halogen atom, R3 is hydrogen atom, R5 is C2-6 alkoxy group, R6 is hydrogen atom, and Y is methylene group benzylidene group substituted by R1.
The compounds according to the present invention are the compounds represented by the formula (I) or salts thereof. Concrete examples of the compounds having combinations of preferable substituents are as follows.
In the formula (I), it is shown a compound or a salt thereof in which A is phenyl group substituted by R1 and R2 or unsubstituted thienyl group; R1 is hydrogen atom, halogen atom, trifluoromethyl group, cyano group, lower alkoxycarbonyl group or trifluoromethoxy group; R2 is hydrogen atom or halogen atom; R3 is hydrogen atom; R4 is methyl group; R5 is straight chain or branched C2-4 alkoxy group with its bonding position at the para-position (4-position) relative to the group xe2x80x94NR4xe2x80x94; R6 is hydrogen atom; R7 is hydrogen atom; R8 is hydrogen atom; X is a single bond; Y is methylene group or benzylidene group substituted by R1; and Z is methylene group. In this case, the formula (I) may be expressed by the formula (II): 
(wherein Axe2x80x2 represents a phenyl group substituted by R1 and R2 or unsubstituted thienyl group, xe2x80x94O(C2-4 Alk) represents straight chain or branched C2-4 alkoxy group, and Ya represents methylene group or benzylidene group substituted by R1).
The second embodiment of the present invention is to provide a pharmaceutical composition comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as active ingredients.
The third embodiment of the present invention is to provide an antiarrythmic agent comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as acective ingredients. The antiarrythmic agent is capable of oral administration.
The fourth embodiment of the present invention is to provide a method for manufacturing a compound represented by the formula (I)-a or a salt thereof which both R7 and R8 in the formula (I) are hydrogen atoms: 
(wherein A, R3, R4, R5, R6, X, Y and Z have the same meanings as defined above), comprising the following process (a) or (b).
Process (a)
A process characterized by reacting the compound represented by the formula (VI): 
(wherein A, R3, X and Z have the same meanings as defined above, R4xe2x80x2 represents hydrogen atom or lower alkyl group, R5xe2x80x2 and R6xe2x80x2 have the same meanings as defined in R5 and R6, or represent lower alkoxycarbonyl group, and Yxe2x80x2 has the same meaning as defined in Y, or represents C1-2 alkylenecarbonyl group or carbonyl group) under reducing conditions.
Process (b)
A process characterized by reacting a compound represented by the formula (VIII): 
(wherein R3, R4xe2x80x2, R5xe2x80x2, R6xe2x80x2 and Z have the same meanings as defined above) under reducing conditions to form a compound represented by the formula (X): 
(wherein R3, R4xe2x80x2, R5, R6 and Z have the same meanings as defined above) and reacting the obtained compound of the formula (X) with a compound represented by the formula (IX): 
(wherein A, X and Yxe2x80x2 have the same meaning as defined above, and Q represent hydrogen atom, hydroxyl group, halogen atom or lower alkyl group) in the presence or absence of a base when xe2x80x94Yxe2x80x2 and -Q together represent halogenated alkyl, in the presence or absence of an acid catalyst under reducing conditions when xe2x80x94Yxe2x80x2 and -Q together represent aldehyde or ketone, or using a condensation agent when xe2x80x94Yxe2x80x2 and -Q together represent carboxylic acid, followed by reduction reaction.
The fifth embodiment of the present invention is to provide a method for manufacturing a compound represented by the following formula (I)-b or a salt thereof which R7 and R8 in the formula (I) are simultaneously hydrogen atom and Z is Zxe2x80x2: 
(wherein A, R3, R4, R5, R6, X and Y have the same meanings as defined above, and Zxe2x80x2 represents methylene group unsubstituted or substituted by a group arbitrarily selected from a group comprising lower alkyl group, lower alkoxy group or unprotected or protected hydroxyl group), and uses the following process (c) or (d).
Process (c)
A process characterized by adding a compound represented by the formula (XI): 
(wherein R4xe2x80x2, R5, R6 and Zxe2x80x2 have the same meanings as defined above and W represents hydrogen atom or halogen atom) to a compound represented by the formula (XII): 
(wherein A, X and Yxe2x80x2 have the same meanings as defined above) and alkylating the generated hydroxy group according to the necessity to obtain a compound represented by the formula (VIxe2x80x2): 
(wherein A, R3, R4xe2x80x2, R5, R6, X, Yxe2x80x2 and Zxe2x80x2 have the same meanings as defined above) and reacting the obtained compound (VIxe2x80x2) under reducing conditions.
Process (d)
A process characterized by adding the compound represented by the formula (XI): 
to a compound represented by the formula (XIII): 
(wherein P represents a protective group used for an amino group) and alkylating the obtained hydroxyl group according to the necessity to obtain a compound represented by the formula (VIIxe2x80x2): 
(wherein R3, R4xe2x80x2, R5, R6, Zxe2x80x2 and P have the same meanings as defined above), and followed by deprotection and reduction reactions to obtain a compound represented by the formula (Xxe2x80x2): 
(wherein R3, R4xe2x80x2, R5, R6 and Zxe2x80x2 have the same meaning as defined above), which is allowed to react with a compound represented by the formula (IX): 
in the presence or absence of a base when xe2x80x94Yxe2x80x2 and -Q together represent halogenated alkyl, in the presence or absence of an acid catalyst under a reducing condition when xe2x80x94Yxe2x80x2 and -Q together represent aldehyde or ketone groups, or using a condensation agent when xe2x80x94Yxe2x80x2 and -Q together represent carboxylic acid, followed by conducting reduction reaction.
The present invention will be described in detail hereinafter. The compounds according to the present invention are compounds represented by the formula (I) or pharmaceutically acceptable salts thereof: 
(wherein A represents phenyl group, naphthyl group or monocyclic aromatic heterocyclic group each substituted by R1 and R2; R1 and R2 each independently represent groups arbitrarily selected from a group comprising hydrogen atom, halogen atom, trifluoromethyl group, cyano group, lower alkoxycarbonyl group, amino group unsubstituted or mono- or di-substituted by lower alkyl group, lower alkanoylamino group unsubstituted or substituted by fluorine atom, unprotected or protected hydroxyl group, lower alkoxy group, lower alkyl group, trifluoromethoxy group, nitro group, phenyl group, phenoxy group, unprotected or protected carboxyl group, carbamoyl group unsubstituted or mono- or di-substituted by lower alkyl group, lower alkanoyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group and sulfamoyl group unsubstituted or mono- or di-substituted by lower alkyl group, or R1 and R2 together represent alkylenedioxy group; R3 represents hydrogen atom or lower alkyl group; R4 represents a hydrogen atom, lower alkyl group or lower alkanoyl group; R5 and R6 each independently represent a group arbitrarily selected from a group comprising hydrogen atom, halogen atom, lower alkoxy group unsubstituted or mono-substituted by unprotected or protected hydroxyl group, lower alkyl group unsubstituted or mono-substituted by unprotected or protected hydroxyl group, phenoxy group, lower alkenyloxy group or unprotected or protected hydroxyl group; X represents a single bond, a group: xe2x80x94CH(OH)xe2x80x94, oxygen atom or carbonyl group; Y represents lower alkylene group, lower alkylidene group or benzylidene group substituted by R1, Y may form 5 or 6-membered ring together with X and carbon atom on a benzene ring when A is phenyl group; Z represents a single bond or methylene group unsubstituted or substituted by a group arbitrarily selected from a group comprising a lower alkyl group, lower alkoxy group or unprotected or protected hydroxyl group; and R7 and R8 each independently represent hydrogen atom or lower alkyl groups, provided that a case that R5 and R6 simultaneously represent hydrogen atoms is excluded).
In the definitions of the groups in the structural formula according to the present invention, the xe2x80x9cmonocyclic aromatic heterocyclicxe2x80x9d means 5 or 6-membered ring containing one or two hetero-atoms and includes, for example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyridyl group or pyrimidinyl group.
The xe2x80x9chalogen atomxe2x80x9d includes fluorine atom, chlorine atom, bromine atom and iodine atom.
The term xe2x80x9clowerxe2x80x9d means straight, branched or cyclic carbon chain with a carbon number of 1 to 6, unless otherwise stated. Accordingly, the xe2x80x9clower alkyl groupxe2x80x9d includes, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, 3-pentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, cyclobutylmethyl group, 2-cyclobutylethyl group or cyclopentylmethyl group.
The term xe2x80x9clower alkyl group mono-substituted by hydroxyl groupxe2x80x9d means a group which an arbitrary hydrogen atom on the lower alkyl group is substituted by hydroxyl group. Examples of it include a hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxy-1-methylethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxy-1-methylpropyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1-hydroxy-1-methylbutyl group, 1-hydroxypentyl group, 2-hydroxypentyl group, 3-hydroxypentyl group, 4-hydroxypentyl group, 5-hydroxypentyl group, 1-hydroxy-1-methylpentyl group, 1-hydroxyhexyl group, 2-hydroxyhexyl group, 3-hydroxyhexyl group, 4-hydroxyhexyl group, 5-hydroxyhexyl group, 6-hydroxyhexyl group, 1-hydroxycyclopropyl group and 1-hydroxycyclopropylmethyl group.
The xe2x80x9clower alkoxycarbonyl groupxe2x80x9d includes a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group, cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cyclopropylmethyloxycarbonyl group, 1-cyclopropylethyloxycarbonyl group, 2-cyclopropylethyloxycarbonyl group, cyclobutylmethyloxycarbonyl group, 2-cyclobutylethyloxycarbonyl group or cyclopentylmethyloxycarbonyl group.
The term xe2x80x9cthe amino group unsubstituted or mono- or di-substituted by lower alkyl groupxe2x80x9d means amino group in which one or two hydrogen atoms of the amino group may be substituted by the xe2x80x9clower alkyl groupxe2x80x9d. Example of it include amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group, isohexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dipentylamino group, ethylmethylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino group, butylethylamino group or butylpropylamino group.
The xe2x80x9clower alkanoylamino group unsubstituted or substituted by fluorine atomsxe2x80x9d include, for example, a formylamino group, acetylamino group, monofluoroacetylamino group, difluoroacetylamino group, trifluoroacetylamino group, propionylamino group, 2-fluoroaropionylamino group, 3-fluoropropionylamino group, 2,2-difluoropropionylamino group, 2,3-difluoropropionylamino group, 3,3,3-trifluoropropionylamino group, 2,2,3,3-tetrafluoropropionylamino group, pentafluoropropionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group, pivaloylamino group or hexanoylamino group.
The xe2x80x9clower alkoxy groupxe2x80x9d include, for example, a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, 3-pentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cyclopropylmethyloxy group, 1-cyclopropylethyloxy group, 2-cyclopropylethyloxy group, cyclobutylmethyloxy group, 2-cyclobutylethyloxy group or cyclopentylmethyloxy group.
The xe2x80x9clower alkoxy group mono-substituted by hydroxyl groupxe2x80x9d means a group in which an arbitrary hydrogen atom except at the 1-position of the lower C2-6 alkoxy group is mono-substituted by hydroxyl group. Examples of it include 2-hydroxyethoxy group, 2-hydroxy-1-methylethoxy group, 2-hydroxypropoxy group, 3-hydroxypropoxy group, 2-hydroxybutoxy group, 3-hydroxybutoxy group, 4-hydroxybutoxy group, 2-hydroxypentyloxy group, 5-hydroxypentyloxy group, 2-hydroxyhexyloxy group, 6-hydroxyhexyloxy group, 2-hydroxycyclopropyloxy group, 2-hydroxycyclobutyloxy group, 2-hydroxycyclopentyloxy group or 3-hydroxycyclopentyloxy group.
The xe2x80x9ccarbamoyl group unsubstituted or mono- or di-substituted by lower alkyl groupsxe2x80x9d means a carbamoyl group in which one or two hydrogen atoms on the nitrogen atom in the carbamoyl group may be substituted by aforesaid xe2x80x9clower alkyl groupxe2x80x9d. Example of it include carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, cyclopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl group, pentylcarbamoyl group, isopentylcarbamoyl group, hexylcarbamoyl group, isohexylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoyl group, diisopropyl-carbamoyl group, dibutylcarbamoyl group, dipentylcarbamoyl group, ethylmethylcarbamoyl group, methylpropylcarbamoyl group, ethylpropylcarbamoyl group, butylmethylcarbamoyl group, butylethylcarbamoyl group, or butylpropylcarbamoyl group.
Examples of the xe2x80x9clower alkanoyl groupxe2x80x9d include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group or hexanoyl group.
Examples of the xe2x80x9clower alkylthio groupxe2x80x9d include a methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, tert-pentylthio group, neopentylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthio group, 1-ethylpropylthio group, hexylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, cyclopropylmethylthio group, 1-cyclopropylethylthio group, 2-cyclopropylethylthio group, cyclobutylmethyl-thio group, 2-cyclobutylethylthio group or cyclopentylmethylthio group.
Examples of the xe2x80x9clower alkylsulfinyl groupxe2x80x9d include a methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, isopropylsulfinyl group, butylsulfinyl group, isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group, pentylsulfinyl group, isopentylsulfinyl group, tert-pentylsulfinyl group, neopentylsulfinyl group, 2-methylbutylsulfinyl group, 1,2-dimetylpropylsulfinyl group, 1-ethylpropylsulfinyl group, hexylsulfinyl group, cyclopropylsulfinyl group, cyclobutylsulfinyl group, cyclopentylsulfinyl group, cyclohexylsulfinyl group, cyclopropylmethylsulfinyl group, 1-cyclopropylethylsulfinyl group, 2-cyclopropylethylsulfinyl group, cyclobutylmethylsulfinyl group, 2-cyclobutylethylsulfinyl group or cyclopentylmethylsulfinyl group.
Examples of the xe2x80x9clower alkylsulfonyl groupxe2x80x9d include a methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, tert-pentylsulfonyl group, neopentylsulfonyl group, 2-methylbutylsulfonyl group, 1,2-dimethylpropylsulfonyl group, 1-ethylpropylsulfonyl group, hexylsulfonyl group, cyclopropylsulfonyl group, cyclobutylsulfonyl group, cyclopentylsulfonyl group, cyclohexylsulfonyl group, cyclopropylmethylsulfonyl group, 1-cyclopropylethylsulfonyl group, 2-cyclopropylethylsulfonyl group, cyclobutylmethylsulfonyl group, 2-cyclobutylethylsulfonyl group or cyclopentylmethlsulfonyl group.
The xe2x80x9csulfamoyl group unsubstituted or mono- or di-substituted by lower alkyl groupxe2x80x9d means a sulfamoyl group in which one or two hydrogen atom on the nitrogen atom in the sulfamoyl group may be substituted by said xe2x80x9clower alkyl groupxe2x80x9d. Examples of it include sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, cyclopropylsulfamoyl group, butylsulfamoyl group, isobutylsulfamoyl group, pentylsulfamoyl group, isopentylsulfamoyl group, hexylsulfamoyl group, isohexylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, dipropylsulfamoyl group, disopropylsulfamoyl group, dibutylsulfamoyl group, dipentylsulfamoyl group, ethylmethylsulfamoyl group, metylpropylsulfamoyl group, ethylpropylsulfamoyl group, butylmethylsulfamoyl group, butylethylsulfamoyl group and butylpropylsulfamoyl group.
Examples of the xe2x80x9calkylenedioxy groupxe2x80x9d include methylenedioxy group or ethylenedioxy group.
The xe2x80x9clower alkenyloxy groupxe2x80x9d means a group in which one of the carbonxe2x80x94carbon bonds in the lower C3-6 alkoxy group is a double bond and the position of which is not at the 1-position. Examples of it include 2-propenyloxy group, 1-methyl-2-propenyloxy group, 2-methyl-2-propenyloxy group, 1,1-dimethyl-2-propenyloxy group, 1,2-dimethyl-2-propenyloxy group, 1,1,2-trimethyl-2-propenyloxy group, 2-butenyloxy group, 1-methyl-2-butenyloxy group, 2-methyl-2-butenyloxy group, 3-methyl-2-butenyloxy group, 3-butenyloxy group, 1-metyl-3-butenyloxy group, 2-pentenyloxy group, 3-pentenyloxy group, 4-pentenyloxy group, 2-cyclopentenyloxy group, 2-hexenyloxy group, 3-hexenyloxy group, 4-hexenyloxy group, 5-hexenyloxy group, 2-cyclohexenyloxy group or 3-cyclohexenyloxy group.
The xe2x80x9clower alkylene or alkylidene groupxe2x80x9d is C1-6 alkylene or C1-6 alkylidene group, and includes methylene group, ethylene group, methylmethylene group, trimethylene group, dimethylmethylene group, tetramethylene group, methyltrimethylene group, ethylethylene group, dimethylethylene group, ethylmethylmethylene group, pentamethylene group, methyltetramethylene group, dimethyltrimethylene group, trimethylethylene group, dimethylmethylene group, hexamethylene group, methylpentamethylene group or dimethyltetramethylene group, and also includes straight-chain or branched ones of these groups.
Examples of the protective group for the xe2x80x9cunprotected or protected hydroxyl groupxe2x80x9d described in the present specification include alkyl protective group such as a methyl group, tert-butyl group, benzyl group, trityl group and methoxymethyl group; silyl protective group such as trimethylsilyl group or tert-butyidimethylsilyl group; acyl protective group such as formyl group, acetyl group or benzoyl group; and carbonate protective group such as methoxycarbonyl group or benzyloxycarbonyl group.
Examples of the protective group for the xe2x80x9cunprotected or protected carboxyl groupxe2x80x9d described in the present specification include alkylester protective groups such as a methyl group, ethyl group, tert-butyl group, benzyl group, diphenylmethyl group or trityl group; and silyl ester protective group such as trimethylsilyl group or tert-butyldimethylsilyl group.
Preferable embodiments in the definitions of the substituents of the compound according to the present invention are as follows.
The A is preferably phenyl group, naphthyl group, furyl group, thienyl group or pyridyl group, more preferably phenyl group or thienyl group, and further preferably phenyl group.
Preferably, R1 and R2 each are hydrogen atom, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyano group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, dimethylamino group, trifluoroacetylamino group, hydroxyl group, methoxy group, isopropoxy group, methyl group, isopropyl group, trifluoromethoxy group, nitro group, phenyl group, phenoxy group, carboxyl group, carbamoyl group, dimethylcarbamoyl group, acetyl group, methylthio group, methylsulfinyl group, methylsulfonyl group or sulfamoyl group, respectively, or R1 and R2 together form methylenedioxy group. More preferably, R1 and R2 each are hydrogen atom, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyano group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, trifluoroacetylamino group, methoxy group, isopropoxy group, methyl group, isopropyl group, trifluoromethoxy group, nitro group or methylthio group. Further preferably, R1 and R2 each are hydrogen atom, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyano group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group or trifluoromethoxy group.
As the combination of R1 and R2, it is preferable that R1 is hydrogen atom, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyano group, methoxycarbony group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, trifluoroacetylamino group, methoxy group, isopropoxy group, methyl group, isopropyl group, trifluoromethoxy group, nitro group or methylthio group, and R2 is hydrogen atom or fluorine atom. More preferably, R1 is hydrogen atom, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyano group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group or trifluoromethoxy group, and R2 is hydrogen atom or fluorine atom.
R3 is preferably hydrogen atom or methyl group, more preferably hydrogen atom.
R4 is preferably hydrogen atom, methyl group, ethyl group, isopropyl group or acetyl group, more preferably methyl group, ethyl group, isopropyl group or acetyl group, and further preferably methyl group, ethyl group or isopropyl group.
R5 is preferably methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, cyclobutoxy group, cyclopropylmethyloxy group, 2-cyclopropylethyloxy group, pentyloxy group, 3-pentyloxy group, isopentyloxy group, 2-methyl-2-butoxy group, cyclohexyloxy group, 3-butenyloxy group, 3-hydroxybutyloxy group, 4-hydroxybutyloxy group, propyl group or phenoxy group; more preferably, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, cyclobutoxy group, cyclopropylmethyloxy group, 2-cyclopropylethyloxy group, pentyloxy group, 3-pentyloxy group, isopentyloxy group, 2-methyl-2-butoxy group or cyclohexyloxy group; and further preferably ethoxy group, propoxy group, isopropoxy group, butoxy group or isobutoxy group.
R6 is preferably hydrogen atom, fluorine atom, hydroxyl group or hydroxymethyl group, more preferably hydrogen atom.
As the combination of R5 and R6, it is preferable that R5 is ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, cyclobutoxy group, cyclopropylmethyloxy group, 2-cyclopropylethyloxy group, pentyloxy group, 3-pentyloxy group, isopentyloxy group, 2-methyl-2-butoxy group or cyclohexyloxy group, and R6 is hydrogen atom. More preferably, R5 is ethoxy group, propoxy group, isopropoxy group, butoxy group or isobutoxy group, and R6 is hydrogen atom.
It is preferable that the binding position of R5 is a para-position relative to xe2x80x94NR4xe2x80x94.
X is preferably a single bond, group: xe2x80x94CH(OH)xe2x80x94, oxygen atom or carbonyl group, more preferably a single bond or group: xe2x80x94CH(OH)xe2x80x94, and further preferably a single bond.
Y is preferably methylene group, ethylene group, methylmethylene group, trimethylene group, benzylidene group or 4xe2x80x2-fluorobenzylidene group, more preferably methylene group, ethylene group, benzylidene group or 4xe2x80x2-fluorobenzylidene group, and further preferably methylene group, benzylidene group or 4xe2x80x2-fluorobenzylidene group.
Y is preferably forms an indanyl group when A is a phenyl group and forms 5 or 6-membered rings together with X and carbon atoms on the benzene ring.
Z is preferably a single bond or methylene group unsubstituted or substituted by methoxy group or hydroxyl group, and is more preferably methylene group.
R7 and R8 each are preferably hydrogen atoms.
As the combination of the substituents, it is preferable that A is a phenyl group, naphthyl group, furyl group, thienyl group or pyridyl group each substituted by R1 and R2, wherein R1 and R2 each are hydrogen atom, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyano group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, dimethylamino group, trifluoroacetylamino group, hydroxyl group, methoxy group, isopropoxy group, methyl group, isopropyl group, trifluoromethoxy group, nitro group, phenyl group, phenoxy group, carboxyl group, carbamoyl group, dimethylcarbamoyl group, acetyl group, methylthio group, methylsulfinyl group, methylsulfonyl group or sulfamoyl group, or R1 and R2 together form methylenedioxy group; R3 is hydrogen atom or methyl group; R4 is hydrogen atom, methyl group, ethyl group, isopropyl group or acetyl group; R5 is methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, cyclobutoxy group, cyclopropylmethyloxy group, 2-cyclopropylethyloxy group, pentyloxy group, 3-pentyloxy group, isopentyloxy group, 2-methyl-2-butoxy group, cyclohexyloxy group, 3-butenyloxy group, 3-hydroxybutyloxy group, 4-hydroxybutyloxy group, propyl group or phenoxy group, and the binding position of R5 is at a para-position (4-position) relative to xe2x80x94NR4xe2x80x94; R6 is hydrogen atom, fluorine atom, hydroxyl group or hydroxymethyl group; R7 is hydrogen atom; R8 is hydrogen atom; X is a single bond; Y is methylene group, ethylene group, benzylidene group or 4xe2x80x2-fluorobenzylidene group; and Z is a single bond or methylene group unsubstituted or substitubed by methoxy group or hydroxyl group.
Further, it is preferable that A is phenyl group or thienyl group each substituted by R1 and R2; R1 and R2 each are hydrogen atom, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyano group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, dimethylamino group, trifluoroacetylamino group, hydroxyl group, methoxy group, isopropoxy group, methyl group, isopropyl group, trifluoromethoxy group, nitro group, phenyl group, phenoxy group, carboxyl group, carbamoyl group, dimethylcarbamoyl group, acetyl group, methylthio group, methylsulfinyl group, methylsulfonyl group or sulfamoyl group, or R1 and R2 together form methylenedioxy group; R3 is hydrogen atom or methyl group; R4 is methyl group, ethyl group or isopropyl group; R5 is methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, cyclobutoxy group, cyclopropylmethyloxy group, 2-cyclopropylethyloxy group, pentyloxy group, 3-pentyloxy group, isopentyloxy group, 2-methyl-2-butoxy group, cyclohexyloxy group, 3-butenyloxy group, 3-hydroxybutyloxy group, 4-hydroxybutyloxy group, propyl group or phenoxy group; R6 is hydrogen atom, fluorine atom, hydroxyl group or hydroxymethyl group; R7 is hydrogen atom; R8 is hydrogen atom; X is a single bond, group: xe2x80x94CH(OH)xe2x80x94, oxygen atom or carbonyl group; Y is methylene group, ethylene group, methylmethylene group, trimethylene group, benzylidene group or 4xe2x80x2-fluorobenzylidene group; Y may form indanyl group when A is phenyl group and forms 5- or 6-membered rings together with X and carbon atoms on the benzene ring; and Z is a single bond or methylene group.
Further, it is preferable that A is phenyl group, naphthyl group, furyl group, thienyl group or pyridyl group each substituted by R1 and R2; R1 is hydrogen atom, fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, cyano group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group or trifluoromethoxy group; R2 is hydrogen atom or fluorine atom; R3 is hydrogen atom; R4 is hydrogen atom, methyl group, ethyl group, isopropyl group or acetyl group; R5 is ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, cyclobutoxy group, cyclopropylmethyloxy group, 2-cyclopropylethyloxy group, pentyloxy group, 3-pentyloxy group, 3-methylbutoxy group, 2-methyl-2-butoxy group or cyclohexyloxy group; R6 is hydrogen atom; R7 is hydrogen atom; R8 is hydrogen atom; X is a single bond, group: xe2x80x94CH(OH)xe2x80x94, oxygen atom or carbonyl group; Y is a methylene group, benzylidene group or 4xe2x80x2-fluorobenzylidene group; and Z is a single bond or methylene group unsubstituted or substituted by methoxy group or hydroxyl group.
While the compounds according to the present invention are compounds represented by the formula (I) or salts thereof, examples of preferable combinations of the substituents are as follows.
In the compounds represented by the formula (I) or salts thereof, A is phenyl group substituted by R1 and R2 or unsubstituted thienyl group; R1 is hydrogen atom, halogen atom, trifluoromethyl group, cyano group, lower alkoxycarbonyl group or trifluoromethoxy group; R2 is hydrogen atom or halogen atom; R3 is hydrogen atom; R4 is methyl group; R5 is straight chain or branched C2-4 alkoxy group, and the binding position of which is at a para-position (4-position) relative to xe2x80x94NR4xe2x80x94; R6 is hydrogen atom; R7 is hydrogen atom; R8 is hydrogen atom; X is a single bond; Y is methylene group or benzylidene group substituted by R1; and Z is methylene group. In this case, the formula (I) may be also expressed as the formula (II): 
(wherein Axe2x80x2 represents a phenyl group substituted by R1 and R2, or unsubstituted thienyl group; xe2x80x94O(C2-4 Alk) represents straight chain or branched C2-4 alkoxy group; and Ya represents methylene group or benzylidene group substituted by R1).
Preferable examples of the compounds of the formula (I) include:
1-benzyl-4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol;
1-benzyl-4-[2-[N-methyl-N-(4-n-propoxyphenyl)amino]ethyl]piperidin-4-ol;
4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-chlorophenylmethyl)piperidin-4-ol;
4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-(trifluoromethyl)phenylmethyl]piperidin-4-ol;
4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-cyanophenylmethyl)piperidin-4-ol;
4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-methoxycarbonylphenylmethyl)piperidin-4-ol;
4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3-fluorophenylmethyl)piperidin-4-ol;
4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(3,4-diflorophenylmethyl)piperidin-4-ol;
4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(4-fluorophenylmethyl)piperidin-4-ol;
4-[2-[N-(4-n-butoxyphenyl)-N-methylamino]ethyl]-1-(2-fluorophenylmethyl)piperidin-4-ol;
1-(4-chlorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
1-(4-bromophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol;
1-(4-fluorophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
1-(4-cyanophenylmethyl)-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(4-nitrophenylmethyl)piperidin-4-ol;
1-[4-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
1-[4-fluoro-3-(trifluoromethyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
1-(4-bromo-2-fluorophenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(2-thienylmethyl)piperidin-4-ol;
4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(3-thienylmethyl)piperidin-4-ol;
1-[2-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
1-[3-(methoxycarbonyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-[4-(isopropoxycarbonyl)phenylmethyl]piperidin-4-ol;
1-[2-fluoro-4-(trifluoromethyl)phenylmethyl]-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
4-[2-[N-methyl-N-(4-ethoxyphenyl)amino]ethyl]-1-[4-(trifluoromethyl)phenylmethyl]piperidin-4-ol;
1-diphenylmethyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol;
1-bis(4-fluorophenyl)methyl-4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]piperidin-4-ol; and
1-diphenylmethyl-4-[2-[N-(4-ethoxyphenyl)-N-methylamino]ethyl]piperidin-4-ol.
These compounds can form salts to be described hereinafter.
The compounds according to the present invention may contain asymmetric carbon atoms, and the present invention contains mixtures of all of optically active or inactive stereoisomers (such as enantiomers and diastereomers), geometrical isomers and tautomers, and isolated compounds thereof. The isolation and purification of the stereoisomers can be made by those skilled in the art by optical resolution using preferential crystallization and column chromatography or by asymmetric synthesis.
The compound (I) according to the present invention may form an acid addition salt. A salt with a base may be also formed depending on the kind of the substituent. The salt is not particularly restricted so long as it is pharmaceutically acceptable. Examples of the salt include acid addition salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; acid addition salts with an organic carboxylic acid such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, formic acid, malic acid, tartaric acid, citric acid or mandelic acid; acid addition salts with an organic sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 2-hydroxyethanesulfonic acid; an acid addition salt with an acidic amino acid such as aspartic acid and glutamic acid; a salt with an alkali metal or alkaline earth metal such as sodium, potassium, magnesium, calcium or aluminum; a salt with an organic base such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine or ornithine; or an ammonium salt. These salts can be formed by conventional methods, for example, mixing of an equivalent compound of the present invention with a solution containing a desired acid or base, and collecting the desired salt by filtration or evaporation of solvents. The compounds of the present invention or salts thereof may form a solvate with a solvent such as water, ethanol or glycerol.
The salts of the compounds of the present invention may contain mono-, di- or tri-salts. The compounds of the present invention may simultaneously form both acid addition salt and salt with a base depending on the substituent on the side chains of the compounds.
Further, the present invention contains hydrates, various pharmaceutically acceptable solvates and polymorphic crystals of the compound (I) may be included in the present invention. Naturally, the present invention is not restricted to the compounds to be described hereinafter and contains all the compound represented by the formula (I) or pharmaceutically acceptable salts thereof.
The manufacturing methods according to the present invention will be described hereinafter together with reaction processes thereof. Definitions of A, R3, R4, R4xe2x80x2, R5, R5xe2x80x2, R6, R6xe2x80x2, R7, R8, W, P, Q, X, Y, Yxe2x80x2, Z and Zxe2x80x2 in the compounds represented by the formulae (I), (I)-a, (I)-b, (VI), (VIxe2x80x2), (VIIxe2x80x2), (VIII), (IX), (X), (Xxe2x80x2), (XI), (XII) and (XIII) on the reaction schemes and descriptions in the MANUFACTURING METHODs 1, 2, 3 and 4 have the same meanings as defined above, unless otherwise stated.
The compounds represented by the formula (I) according to the present invention and salts thereof can be manufactured from the compounds represented by the formula (III) (in which R4xe2x80x2, R5xe2x80x2 and R6xe2x80x2 have the same meanings as defined above), formula (IIIxe2x80x2) (in which R4xe2x80x2, R5 and R6 have the same meanings as defined above), formula (IV) (in which A, R3, X, Yxe2x80x2 and Z have the same meanings as defined above), formula (V) (in which R3, P and Z have the same meanings as defined above), formula (XI), formula (XII), formula (XIII), formula (XIV) (in which A, R3, R7, X, Yxe2x80x2 and Z have the same meanings as defined above), formula (XV) (in which R3, R7, P and Z have the same meanings as defined above), formula (XVIII) (in which A, R7, R8, X and Yxe2x80x2 have the same meanings as defined above) and formula (XIX) (in which R7, R8 and P have the same meanings as defined above), which may be synthesized starting from the compounds known in the art or from commertially available compounds, by each method of the MANUFACTURING METHODs 1, 2, 3 and 4, or by modifications thereof. The starting materials, intermediate products and final products may be manipulated as salts, according to the necessity.
The manufacturing methods will be described in detail hereinafter.
 less than MANUFACTURING METHOD 1 greater than 
The compounds which R7 and R8 in the formula (I) represent hydrogen atom are represented by the formula (I)-a, and the manufacturing method thereof is shown below. 
The compound represented by the formula (I)-a and the salt thereof can be manufactured from the compound represented by the formulae (III) and (IV), or (III) and (V) according to the processes in the reaction scheme I 
 less than Process 1 greater than 
The compound represented by the formula (VI) can be produced by reacting the compound represented by the formula (III) with the compound represented by the formula (IV) using a condensation agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water soluble carbodiimide hydrochloride, WSC.HCl) or dicyclohexylcarbodiimide (DCC) in a solvent that does not take part in the reaction, e.g., a halogenated hydrocarbon solvent such as methylene chloride and chloroform, an ether solvent such as diethyl ether and tetrahydrofuran, a hydrocarbon solvent such as benzene and hexane, or a polar solvent such as dimethylformamide and dimethylsulfoxide in a temperature range of 0xc2x0 C. to a reflux temperature of the reaction mixture.
This reaction may proceed using a dehydrating agent such as phosphorus oxychloride in the solvent that does not take part in the reaction including the halogenated hydrocarbon solvent such as methylene chloride and chloroform, ether solvent such as diethyl ether and tetrahydrofuran or the hydrocarbon solvent such as benzene and hexane in a temperature range of xe2x88x9220xc2x0 C. to a reflux temperature of the reaction mixture in the presence of a base such as pyridine and triethylamine.
The compound represented by the formula (VI) can be also produced by converting the compound represented by the formula (IV) into an acid chloride using thionyl chloride and by reacting the acid chloride obtained with the compound represented by the formula (III) in the presence of an organic base such as triethylamine and pyridine or an inorganic base such as potassium carbonate in the halogenated hydrocarbon solvent such as methylene chloride and chloroform, ether solvent such as diethyl ether and tetrahydrofuran or hydrocarbon solvent such as benzene and hexane, or in a basic solvent such as pyridine and triethylamine in a temperature range of xe2x88x9220xc2x0 C. to a reflux temperature of the reaction mixture.
The compound represented by the formula (VI) may be also manufactured according to the  less than Process 2 greater than ,  less than Process 3 greater than  and  less than Process 4 greater than  to be described hereinafter.
 less than Process 2 greater than 
The compound represented by the formula (VII) (in which R3, R4, R5xe2x80x2, R6xe2x80x2, P and Z have the same meaning as defined above) can be manufactured from the compound represented by the formula (III) and the compound represented by the formula (V) in accordance with the method in the  less than Process 1 greater than . As the protective group P, an appropriate protective group described in the general remarks of xe2x80x9cProtective Groups in Organic Synthesis, 3rd edition, edited by T. W. Green and P. G. M. Wuts, published by John Wiley and Sons, 1999xe2x80x9d may be used. Such protective group includes an alkyl protective group such as a benzyl group, trityl group and methoxymethyl group, and a carbamate protective group such as a tert-butoxycarbonyl group and benzyloxycarbonyl group.
 less than Process 3 greater than 
The compound represented by the formula (VIII) can be produced by de-protection of the position 1 of piperidine ring of the compound represented by the formula (VII).
The position 1 of piperidine ring of the compound represented by the formula (VII) can be de-protected in accordance with the method described in the general remarks of xe2x80x9cProtective Groups in Organic Synthesis, 3rd edition, 1999xe2x80x9d. The compound represented by the formula (VIII) can be produced by a de-protection reaction using a catalyst such as palladium on carbon or platinum oxide in an alcoholic solvent such as methanol and ethanol, or a solvent such as ethyl acetate, acetic acid and water under hydrogen atmosphere or in the presence of ammonium formate in a temperature range from 0xc2x0 C. to a reflux temperature of the reaction mixture, when the protective group (P in the formula) is, for example, benzyl group or benzyloxycarbonyl group. Alternatively, the compound represented by the formula (VIII) can be produced by a de-protection reaction using an acid such as trifluoroacetic acid or hydrochloric acid in the presence or absence of anisole in a temperature range from 0xc2x0 C. to a reflux temperature of the reaction mixture, when the protective group (P in the formula) is, for example, tert-butoxycarbonyl group.
 less than Process 4 greater than 
The compound represented by the formula (VIII) can be reacted with the compound represented by the formula (IX) by the following methods depending on the kind of xe2x80x94Yxe2x80x2 and -Q.
(Method A): The compound represented by the formula (VI) can be produced by reacting the compound represented by the formula (VIII) with the compound represented by the formula (IX) in the presence or absence of the organic base such as triethylamine and pyridine or inorganic base such as potassium carbonate in a solvent that does not take part in the reaction, e.g., the halogenated hydrocarbon solvent such as methylene chloride and chloroform, ether solvent such as diethyl ether and tetrahydrofuran, hydrocarbon solvent such as benzene and hexane, or polar solvent such as dimethylformamide and dimethylsulfoxide in a temperature range from 0xc2x0 C. to a reflux temperature of the reaction mixture, when xe2x80x94Yxe2x80x2 and -Q together represent halogenated alkyl. Sodium iodide may be used as a catalyst thereat.
(Method B): The compound represented by the formula (VI) can be produced by reacting the compound represented by the formula (VIII) with the compound represented by the formula (IX) using an appropriate reducing agent in the presence or absence of the acid catalyst such as acetic acid in a solvent, e.g., aromatic hydrocarbon solvent such as benzene and toluene, halogenated hydrocarbon solvent such as methylene chloride and chloroform, or alcoholic solvent such as methanol and ethanol, when xe2x80x94Yxe2x80x2 and -Q together represent aldehyde or ketone. While any reducing agents capable of reducing an imino group into an amino group may be generally used, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride and sodium cyanoborohydride are preferable among the reducing agents. The reducing reaction can be conducted in the temperature range from xe2x88x9278xc2x0 C. to room temperature, preferably at room temperature and for the enough time to proceed the reaction sufficiently, concretely from 3 to 12 hours.
(Method C): The compound represented by the formula (VI) can be produced in accordance with the method in the  less than Process 1 greater than , when xe2x80x94Yxe2x80x2 and -Q together represent carboxylic acid.
(Process 5)
The compound represented by the formula (I)-a or a salt thereof can be manufactured by reacting the compound represented by the formula (VI) using a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, and a borane complex represented by borane-methyl sulfide complex and borane-tetrahydrofuran complex in a solvent that does not take part in the reaction, e.g., ether solvent such as diethyl ether and tetrahydrofuran or an aromatic hydrocarbon solvent such as toluene and benzene in a temperature range from 0xc2x0 C. to a reflux temperature of the reaction mixture.
When Yxe2x80x2 represents an alkylenecarbonyl group or carbonyl group in the compound represented by the formula (VI), Yxe2x80x2 is simultaneously reduced under the reaction condition employed to afford a compound in which Y is corresponding lower alkylene group.
When R5 or R6xe2x80x2 represent lower alkoxycarbonyl groups, the ester group is reduced simultaneously with the reduction of the amide bonding to be converted to a corresponding alcoholic group. The reduction can proceed by the same method after hydrolyzing the ester group to the carboxyl group. Methods known in the art, for example treating the compound in an alcoholic solvent such as methanol and ethanol in the presence of an aqueous lithium hydroxide or sodium hydroxide at a temperature from room temperature to a reflux temperature of the reaction mixture, may be used for hydrolysis.
The compound represented by the formula (I)-a or a salt thereof can be also produced using the compound represented by the formula (VIII) through the  less than Process 6 greater than  and  less than Process 7 greater than  shown below.
 less than Process 6 greater than 
The compound represented by the formula (X) can be produced from the compound represented by the formula (VIII) according to the method in the  less than Process 5 greater than .
The compound represented by the formula (X) can be also produced by reducing the compound represented by the formula (VII) in accordance with the method in the  less than Process 5 greater than , followed by de-protection of the position 1 of piperidine ring of the obtained compound in accordance with the method in the  less than Process 3 greater than .
 less than Process 7 greater than 
The compound represented by the formula (I)-a or a salt thereof can be produced from the compounds represented by the formulae (X) and (IX). The compound represented by the formula (I)-a can be produced by the Methods A or B in the  less than Process 4 greater than  when xe2x80x94Yxe2x80x2 and -Q together represent halogenated alkyl group, aldehyde or ketone. When xe2x80x94Yxe2x80x2 and -Q together represent carboxylic acid, the compound can also be produced by reducing an amide bonding subsequently produced from the method of the Method C in the  less than Process 4 greater than  in accordance with the method of the  less than Process 5 greater than .
 less than MANUFACTURING METHOD 2 greater than 
The method for manufacturing the compound represented by the formula (I)-b is described hereinafter, wherein R7 and R8 represent hydrogen atoms and Z is denoted by Zxe2x80x2 in the compound represented by the formula (I). 
The compound represented by the formula (I)-b or a salt thereof can be manufactured from the compound represented by the formulae (XI) and (XII), or (XI) and (XIII) according to each manufacturing process in the Reaction Scheme 2. 
 less than Process 1 greater than 
The compound represented by the formula (VIxe2x80x2) can be produced by an addition reaction between the compound represented by the formula (XI) and the compound represented by the formula (XII), followed by alkylation of the hydroxyl group produced according to the necessity. When W is hydrogen atom in the compound represented by the formula (XI), the addition reaction is performed by reacting the compound represented by the formula (XI) with a metal amide reagent such as lithium diisopropylamide, lithium hexamethyldisilazide and potassium hexamethyldisilazide, or an organometallic reagent represented by tin (II) trifulate to form a metal enolate in a solvent that does not take part in the reaction, e.g., an ether solvent such as diethyl ether and tetrahydrofuran or a hydrocarbon solvent such as benzene and hexane in a temperature range from xe2x88x92100xc2x0 C. to room temperature, followed by reacting the reaction product with the compound represented by the formula (XII) in a temperature range from xe2x88x92100xc2x0 C. to room temperature.
When W is halogen atom, preferably bromine atom, in the compounds represented by the formula (XI), the addition reaction is performed by reacting the compound represented by the formula (XI) with zinc powder to form a zinc compound in a solvent that does not take part in the reaction including an ether solvent such as diethyl ether and tetrahydrofuran or a hydrocarbon solvent such as benzene and hexane, followed by reacting the reaction product with the compound represented by the formula (XII).
Alkylation of the tertiary hydroxyl group produced by the addition reaction can be performed using an alkylating agent such as an alkyl halide represented by methyl iodide or an alkyl sulfate represented by dimethyl sulfate in the presence of a base such as sodium hydride in a solvent that does not take part in the reaction such as dimethylformamide or dimethylimidazolidone in a temperature range from xe2x88x9220xc2x0 C. to a reflux temperature of the reaction mixture, preferably in a temperature range from an ice-cooled temperature to room temperature.
The compound represented by the formula (VIxe2x80x2) can be also produced by the methods in the  less than Process 2 greater than ,  less than Process 3 greater than  and  less than Process 4 greater than  to be described hereinafter.
 less than Process 2 greater than 
The compound represented by the formula (VIIxe2x80x2) can be produced from the compounds represented by the formulae (XI) and (XIII) in accordance with the methods in the  less than Process 1 greater than .
 less than Process 3 greater than 
The compound represented by the formula (VIIIxe2x80x2)(in which R3, R4, R5, R6 and Zxe2x80x2 have the same meanings as defined above) can be produced from the compounds represented by the formula (VIIxe2x80x2) in accordance with the  less than Process 3 greater than  in the MANUFACTURING METHOD 1.
 less than Process 4 greater than 
The compound represented by the formula (VIxe2x80x2) can be produced from the compounds represented by the formulae (VIIIxe2x80x2) and (IX) in accordance with the  less than Process 4 greater than  in the MANUFACTURING METHOD 1.
 less than Process 5 greater than 
The compound represented by the formula (I)-b or a salt thereof can be produced from the compound represented by the formula (VIxe2x80x2) in accordance with the  less than Process 5 greater than  in the MANUFACTURING METHOD 1.
The compound represented by the formula (I)-b or a salt thereof can be also produced from the compound represented by the formula (VIIIxe2x80x2) in accordance with the  less than Process 6 greater than  and  less than Process 7 greater than  to be described hereinafter.
 less than Process 6 greater than 
The compound represented by the formula (Xxe2x80x2) can be also produced from the compound represented by the formula (VIIIxe2x80x2) in accordance with the method in the  less than Process 5 greater than .
The compound represented by the formula (Xxe2x80x2) is also produced by reducing the compound represented by the formula (VIIxe2x80x2) in accordance with the method in the  less than Process 5 greater than , followed by de-protection of the position 1 of piperidine ring in accordance with the method in the  less than Process 3 greater than .
 less than Process 7 greater than 
The compound represented by the formula (I)-b or a salt thereof can be produced from the compounds represented by the formulae (Xxe2x80x2) and (IX) in accordance with the method in the  less than Process 7 greater than  in the MANUFACTURING METHOD 1.
 less than MANUFACTURING METHOD 3 greater than 
The method for manufacturing the compound represented by the formula (I)-c is described hereinafter, wherein R8 in the formula (I) represents hydrogen atom. 
The compound represented by the formula (I)-c (in which A, R3, R4, R5, R6, R7, X, Y and Z have the same meanings as defined above) or a salt thereof can be produced from the compounds represented by the formulae (IIIxe2x80x2) and (XIV), or (IIIxe2x80x2) and (XV) in accordance with each manufacturing process in the Reaction Scheme 3. 
 less than Process 1 greater than 
The compound represented by the formula (I)-c or a salt thereof can be produced from the compounds represented by the formulae (IIIxe2x80x2) and (XIV) in accordance with the Method B described in the  less than Process 4 greater than  of the MANUFACTURING METHOD 1.
The compound represented by the formula (I)-c can be produced by subsequently reducing the amide bonding in accordance with the method in the  less than Process 5 greater than  of the MANUFACTURING METHOD 1, when Yxe2x80x2 represents alkylenecarbonyl group or carbonyl group.
The compound represented by the formula (I)-c or a salt thereof can be also produced in accordance with the  less than Process 2 greater than ,  less than Process 3 greater than  and  less than Process 4 greater than  to be described below.
 less than Process 2 greater than 
The compound represented by the formula (XVI) (in which R3, R4, R5, R6, R7, P and Z have the same meanings as defined above) can be produced from the compounds represented by the formulae (IIIxe2x80x2) and (XV) in accordance with the method in the  less than Process 1 greater than .
 less than Process 3 greater than 
The compound represented by the formula (XVII) (in which R3, R4, R5, R6, R7 and Z have the same meanings as defined above) can be produced from the compound represented by the formula (XVI) in accordance with the method in the  less than Process 3 greater than  in the MANUFACTURING METHOD 1.
 less than Process 4 greater than 
The compound represented by the formula (I)-c or a salt thereof can be produced from the compounds represented by the formulae (XVII) and (IX) in accordance with the method in the  less than Process 7 greater than  in the MANUFACTURING METHOD 1.
 less than MANUFACTURING METHOD 4 greater than 
The compound which Z in the formula (I) represents a single bond is represented by the formula (I)-d, and the method for manufacturing thereof will be described hereinafter. 
The compound represented by the formula (I)-d (in which A, R3, R4, R5, R6, R7, R8, X and Y have the same meaning as defined above) and a salt thereof can be produced from the compounds represented by the formulae (IIIxe2x80x2) and (XVIII), or (IIIxe2x80x2) and (XIX) in accordance with the manufacturing processes in the Reaction Scheme 4. 
 less than Process 1 greater than 
The compound represented by the formula (I)-d or a salt thereof can be produced by reacting the compound represented by the formula (IIIxe2x80x2) with the compound represented by the formula (XVIII) in the presence of an acid catalyst or a base catalyst in a solvent that does not take part in the reaction, e.g., halogenated hydrocarbon solvent such as methylene chloride and chloroform, an ether solvent such as diethyl ether and tetrahydrofuran, a hydrocarbon solvent such as benzene and hexane, or a polar solvent such as dimethylformamide and dimethylsulfoxide in a temperature range from 0xc2x0 C. to a reflux temperature of the reaction mixture. The compound may be also produced by a reaction in accordance with the method described by Gary H. Posner et al, in Journal of the American Chemical Society, Vol. 99, pp8208-8214, 1977 in diethyl ether in the presence of neutral alumina at room temperature.
The compound represented by the formula (I)-d can be produced by succeeding reduction of the amide bonding in accordance with the method in the  less than Process 5 greater than  in the MANUFACTURING METHOD 1 when Yxe2x80x2 represents an alkylenecarbonyl group or a carbonyl group.
The compound represented by the formula (I)-d or a salt thereof can be also produced in accordance with the  less than Process 2 greater than ,  less than Process 3 greater than  and  less than Process 4 greater than  to be described hereinafter.
 less than Process 2 greater than 
The compound represented by the formula (XX) (in which R3, R4, R5, R6, R7, R8 and P have the same meanings as defined above) can be produced from the compounds represented by the formulae (IIIxe2x80x2) and (XIX) in accordance with the method in the  less than Process 1 greater than .
 less than Process 3 greater than 
The compound represented by the formula (XXI) (in which R3, R4, R5, R6, R7 and R8 represent the same meanings as hitherto described) can be produced from the compound represented by the formula (XX) in accordance with the method in the  less than Process 3 greater than  in the MANUFACTURING METHOD 1.
 less than Process 4 greater than 
The compound represented by the formula (I)-d and a salt thereof can be produced from the compounds represented by the formulae (XXI) and (IX) in accordance with the method in the  less than Process 7 greater than  in the MANUFACTURING METHOD 1.
The compound synthesized in each manufacturing method above can be converted in each process of each manufacturing process according to the method to be described hereinafter.
Among the compounds represented by the formulae (I)-a, (I)-b, (I)-c, (I)-d, (XVI) and (XX), the compounds in which R4 represents hydrogen atom can be converted to compounds in which R4 is lower alkyl group using an alkylating agent such as an alkyl halide represented by methyl iodide, or an alkyl sulfate represented by dimethyl sulfate in a solvent that does not take part in the reaction, e.g., a halogenated hydrocarbon solvent such as methylene chloride and chloroform, an ether solvent such as diethyl ether and tetrahydrofuran, a hydrocarbon solvent such as benzene and hexane, or a polar solvent such as dimethylformamide and dimethylsulfoxide in the presence of an inorganic base such as potassium hydroxide, sodium hydride and potassium carbonate or an organic base such as triethylamine and pyridine in a temperature range from 0xc2x0 C. to a reflux temperature of the reaction mixture. The compounds can also be converted to compounds in which R4 represents a lower alkyl group using aldehyde derivative or ketone derivative by conducting reaction in accordance with the Method B described in the  less than Process 4 greater than  in the MANUFACTURING METHOD 1. By an acylation reaction in accordance with the method described in the  less than Process 1 greater than  in the MANUFACTURING METHOD 1, the compounds may be also converted to compounds in which R4 represents a lower alkanoyl group using a carboxylic acid derivative. At that time, the compounds obtained by the process above may be converted to the compounds in which R4 represents a lower alkyl group by subsequently applying a reduction treatment described in the  less than Process 5 greater than  in the MANUFACTURING METHOD 1.
Among the compounds represented by the formulae (VI), (VII), (VIxe2x80x2) and (VIIxe2x80x2), compounds in which R4xe2x80x2 is hydrogen atom can be alkylated to be converted to compounds in which R4xe2x80x2 is lower alkyl group using an alkylating agent such as an alkyl halide represented by methyl iodide or an alkyl sulfate represented by dimethyl sulfate in the presence of a base such as potassium hydroxide and sodium hydride in a solvent that does not take part in the reaction including a halogenated hydrocarbon solvent such as methylene chloride and chloroform, an ether solvent such as diethyl ether and tetrahydrofuran, a hydrocarbon solvent such as benzene and hexane, or a polar solvent such as dimethylformamide and dimethylsulfoxide in a temperature range from 0xc2x0 C. to a reflux temperature of the reaction mixture.
Among the compounds represented by the formulae (I)-a, (I)-b, (I)-c, (I)-d, (VI), (VII), (VIxe2x80x2), (VIIxe2x80x2), (XVI) and (XX), compounds which contain alkoxy group on the benzene ring as a substituent can be converted, after de-alkylation using boron tribromide or hydrobromic acid-acetic acid, etc., to other alkoxy substituted form in the presence of a base such as sodium hydride using the alkylating agents described above in a solvent that does not take part in the reaction such as dimethylformamide and dimethylimidazolidone in a temperature range from xe2x88x9220xc2x0 C. to a reflux temperature of the reaction mixture, preferably from an ice-cooled temperature to room temperature. At that time, the compounds may be also converted to lower alkoxy compounds substituted by hydroxyl groups by reducing with lithium aluminum hydride, sodium borohydride or the like, after alkylation with an alkyl halide having oxygen functional group represented by bromoacetic acid ester or bromoacetone as an alkylation agent.
Among each compound produced by each method described above, compounds which X represents carbonyl group can be converted to group: xe2x80x94CH(OH)xe2x80x94 by reacting the compounds in a temperature range from 0xc2x0 C. to a reflux temperature of the reaction mixture in an alcoholic solvent such as methanol and ethanol using a reducing agent such as sodium borohydride according to the necessity.
Among each compound produced each method described above, compound which contain lower alkoxycarbonyl group as a substituent can be converted to a carboxyl group by conventional methods, for example, by hydrolysis in the presence of an aqueous alkali solution such as aqueous solution of lithium hydroxide or sodium hydroxide in an alcoholic solvent such as methanol and ethanol in a temperature range from room temperature to a reflux temperature of the reaction mixture. The obtained carboxyl group can be converted to a carbamoyl group that may be unsubstituted or mono- or di-substituted by lower alkyl groups by a condensation reaction in accordance with the method described in the Method C.
Among the compounds manufactured by the methods as hitherto described, compounds which contain halogen atoms, preferably bromine atoms, as substituents on the aromatic ring, the bromine atom can be converted to cyano group by conventional methods, for example, by reacting the compound using copper (I) cyanate or potassium cyanate in a solvent that does not take part in the reaction, e.g., a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide and dimethylimidazolidone in a temperature range from room temperature to a reflux temperature of the reaction mixture. In this reaction, transition metal complexes such as a palladium complex represented by palladium acetate and nickel complex represented by tetrakistriphenylphosphine nickel may be used as catalysts. The cyano group can be further converted to lower alkanoyl group by reacting the compound with an organometallic compound represented by alkyl magnesium bromide and alkyl lithium in a solvent that does not take part in the reaction including ether solvents such as diethyl ether and tetrahydrofuran in a temperature range from xe2x88x92100xc2x0 C. to room temperature.
When the compounds manufactured in each manufacturing method as hitherto described contain reactive groups such as hydroxyl group, amino group and carboxyl group, these substituents can be appropriately protected in each manufacturing process, and the protective groups can be removed at an appropriate reaction process. While these protective groups may be appropriately introduced and eliminated depending on the type of the protected group or protection group, the methods available are described, for example, in Protective Groups in Organic Synthesis, 3rd edition, 1999.
Among the intermediate compounds to be used in each manufacturing process, the compound represented by the formula (XII) may be produced in accordance with the method known in the art. For example, the compound can be produced by reacting 4-piperidone or its equivalence with the compound represented by the formula (IX) in accordance with the method described in the  less than Process 4 greater than  in the MANUFACTURING METHOD 1. Alternatively, Compound represented by the formula (XII) in which Yxe2x80x2 representes Y can be produced from the compound represented by the following formula (XXII) in accordance with a reaction described by Huegi et al., in Journal of Med. Chem., Vol. 26, p42, 1983: 
(wherein A, X and Y have the same meanings as defined above.)
The compounds represented by the formulae (IV) and (V) can be produced by reacting the compounds represented by the formulae (XII) and (XIII) with unprotected or protected acetic acid having a desired substituent in accordance with the method described in the MANUFACTURING METHOD 2.